Synthesis and anticancer activity of brefeldin A ester derivatives.

Ester derivatives of brefeldin A (BFA) were synthesized to determine which of its two hydroxyl groups could be modified while still maintaining biological activity. The compounds were tested for antiproliferative activity in the National Cancer Institute's 60 cancer cell line screen. Monoderivatization at the C4 and C7 alcohols was tolerated, yielding biologically active compounds, whereas the analogues derivatized at both positions were the least active in the series. Molecular modeling of the analogues revealed that both the C4 and C7 derivatives were well tolerated at the interface between ARF1 and its guanine nucleotide exchange factor ARNO. The Golgi-disruptive properties of the analogues were determined using fluorescence imaging assays. The BFA ester conjugates synthesized in this study were cytotoxic to cancer cells, and we have shown that the disruption of the Golgi complex is not necessary for cytotoxicity. The brefeldin A ester derivatives are potential anticancer agents.